Anti-tumor activity of PM01183 (lurbinectedin) in BRCA1/2-associated metastatic breast cancer patients: results of a single-agent phase II trial

Background

PM01183 (lurbinectedin) is a new anticancer drug that blocks trans-activated transcription, induces DNA double-strand breaks and modulates the tumor microenvironment. PM01183 activity has been observed in different tumor types, and in patients resistant to platinum-based chemotherapy (CT). The activity observed against homologous-recombination-deficient cell lines prompted a phase II trial in metastatic breast cancer (MBC) patients (pts) with deleterious germline BRCA mutations (BRCA+).

Methods

BRCA+ MBC pts pretreated with ≤ 3 CT regimens in the advanced/metastatic setting, measurable disease per RECIST v1.1, performance status (PS) ≤ 1, and adequate major organ function were treated with PM01183 IV q3wk. A protocol amendment adjusted the starting dose from 7 mg fixed dose (FD) to 3.5 mg/m² to improve safety. Primary endpoint was overall response rate (ORR) by RECIST v1.1 with further development of PM01183 if ≥ 17 responses of 53 evaluable pts were confirmed.

Results

As of May 2016, 54 eligible pts (median age 43 years, median 1 prior advanced CT) have been treated (35 with 7 mg FD; 19 with 3.5 mg/m2). PS 0: 30 pts; prior anthracyclines: 45 pts, taxanes: 47 pts, platinum: 27 pts, PARP inhibitors: 9 pts; >2 metastatic sites: 33; BRCA 1: 30 pts; triple negative: 31 pts.

Most common grade (G) 3–4 related adverse events (7 mg FD / 3.5 mg/m²) were (%): neutropenia 71 / 50 (G4: 51/6); febrile neutropenia 29 / 6; thrombocytopenia 26 / 6 (G4; 20/0); G3 fatigue 17 / 17; transaminase increase 26 / 11 (G4; 3/0); and G3 nausea 9 / 6.

Conclusions

Primary endpoint was met. PM01183 is an active drug in BRCA+ MBC, regardless of prior platinum treatment. At 3.5 mg/m², the tolerance improved notably, while maintaining the efficacy. Further development is warranted in this indication and a Phase 3 trial is planned.

Clinical trial identification

NCT01525589

Legal entity responsible for the study

PharmaMar S.A.

Funding

PharmaMar S.A.

Disclosure

J. Balmaña: Receipt of grants / research supports; PharmaMar. Paticipation in a company sponsored speaker's bureau; AstraZeneca.

C.M. Fernandez: PharmaMar employee. C. Kahatt, S. Szyldergemajn, A. Soto-Matos: PharmaMar employee and stock ownership. A. Perez de la Haza: PharmaMar employee. All other authors have declared no conflicts of interest.